The goal of this research is to develop compounds that lower hepatic and renal glucose production through the inhibition of fructose-1,6- bisphosphatase (FBPase), one of the penultimate enzymes in the gluconeogenesis pathway leading to the production of glucose. Such compounds would be useful in the treatment of diabetes, particularly Type II diabetes. Strategies are proposed for the identification of novel FBPase inhibitors through synthesis and high throughput screening of proprietary small molecule libraries, and optimization of these agents through a combination of combinatorial and medicinal chemistry guided by molecular modeling and determination of the crystal structures of enzyme:inhibitor complexes. Preliminary library screening efforts have uncovered a series of reversible non-carbohydrate, non-nucleoside inhibitors of human FBPase. We propose to further investigate and optimize this novel FBPase inhibitor series and to continue the discovery process towards other structural classes of inhibitors by continued high throughput screening of our libraries. PROPOSED COMMERCIAL APPLICATIONS: Because of the large number of people suffering from diabetes in the US and worldwide, and a relative paucity of treatment options (see pages 13- 15), the need for new diabetes therapeutics is large, particularly in the case of Type II diabetes. The research we propose is expected to lead to the identification of novel inhibitors of glucose production, through inhibition of fructose-1,6-bisphosphatase, which could be used in the treatment of diabetes.